4.1. Therapeutic indications

Isatuximab is indicated:

- in combination with pomalidomide and dexamethasone, for the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on the last therapy.

- in combination with carfilzomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy (see section 5.1).

- in combination with bortezomib, lenalidomide, and dexamethasone, for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.

- in combination with bortezomib, lenalidomide, and dexamethasone, for the induction treatment of adult patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant.

4.2. Posology and method of administration

Treatment with isatuximab should be prescribed by a specialist in the treatment of malignancies.

Isatuximab subcutaneous should be administered by a healthcare professional. For the first dose only, immediate access to medical support should be available to manage systemic administration reactions (SARs) if they occur (see section 4.4).

Once the cycle 1 is completed, subsequent subcutaneous injections may be administered at the patient's home by a healthcare professional, as deemed appropriate, provided there were no SAR in the previous cycle.

Premedication

Prevention of systemic administration reaction

Premedication should be used prior to the subcutaneous administration with the following medicinal products to reduce the risk and severity of systemic administration reactions (SAR) (see section 4.4):

• Dexamethasone 40 mg (or 20 mg for patients ≥75 years of age): when administered in combination with isatuximab and pomalidomide,

Dexamethasone 20 mg: when administered in combination with isatuximab and carfilzomib.

Dexamethasone 20 mg: when administered in combination with isatuximab, bortezomib, and lenalidomide.

• Montelukast 10 mg oral (or equivalent), at cycle 1 only.

• Acetaminophen 650 mg to 1000 mg oral (or equivalent).

• Diphenhydramine 25 mg to 50 mg intravenous or oral (or equivalent [e.g., cetirizine, promethazine, dexchlorpheniramine]). The intravenous use of diphenhydramine is preferred for at least the first 4 administrations of isatuximab subcutaneous.

The above recommended dose of dexamethasone corresponds to the total dose to be administered only once before the isatuximab subcutaneous administration, as part of the premedication and of the backbone treatment, before isatuximab and pomalidomide, before isatuximab and carfilzomib, and before isatuximab, bortezomib, and lenalidomide administration.

The recommended premedication agents should be administered 15 ‒ 60 minutes prior to starting an isatuximab subcutaneous administration. Patients who do not experience a SAR upon their first 4 administrations of isatuximab subcutaneous may have their need for subsequent premedication reconsidered.

Management of neutropenia

Dose delay or omission of isatuximab subcutaneous, and the use of colony-stimulating factors (e.g. G-CSF) according to local guidelines may be required to allow recovery of blood cell counts in the event of haematological toxicity (see section 4.4).

Prevention of infection

Antibacterial and antiviral prophylaxis (such as herpes zoster prophylaxis) should be considered during treatment (see section 4.4).

Posology

The recommended dose of isatuximab subcutaneous is 1400 mg administered as subcutaneous injection with CirCLIQ On-Body Delivery System (OBDS) or with a syringe and infusion set for manual administration. Isatuximab subcutaneous is administered in combination with pomalidomide and dexamethasone (Isa-SC + Pd) or in combination with carfilzomib and dexamethasone (Isa-SC + Kd), or in combination with bortezomib, lenalidomide, and dexamethasone (Isa-SC + VRd).

Patients may start treatment using intravenous or subcutaneous isatuximab. Patients currently receiving intravenous isatuximab may switch to subcutaneous isatuximab, at any time during their treatment, once cycle 1 is completed.

Isatuximab subcutaneous (SC) dosing schedules are provided in Tables 1, 2 and 3.

Table 1: Dosing schedule in combination with pomalidomide and dexamethasone or in combination with carfilzomib and dexamethasone

Cycles

Dosing schedule

Cycle 1 (28-day cycle)

1400 mg SC weekly; days 1, 8, 15 and 22

Cycle 2 and beyond (28-day cycle)

1400 mg SC every 2 weeks; days 1, 15

Each treatment cycle consists of a 28-day period. Treatment is repeated until disease progression or unacceptable toxicity.

Table 2: Dosing schedule in combination with bortezomib, lenalidomide, and dexamethasone for patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for autologous stem cell transplant (ASCT)

Cycles

Dosing schedule

Cycle 1 (42-day cycle)

1400 mg SC; days 1, 8, 15, 22, and 29

Cycles 2 to 4 (42-day cycles)

1400 mg SC every 2 weeks; days 1, 15, and 29

Cycles 5 to 17 (28-day cycles)

1400 mg SC every 2 weeks; days 1 and 15

Cycles 18 and beyond (28-day cycles)

1400 mg SC every 4 weeks; day 1

Each treatment cycle consists of a 42-day period from cycle 1 to 4, and of a 28-day period from cycle 5. Treatment is repeated until disease progression or unacceptable toxicity.

Table 3: Dosing schedule in combination with bortezomib, lenalidomide, and dexamethasone for patients with NDMM who are eligible for ASCT

Cycles

Dosing schedule

Induction treatment

Cycle 1 (42-day cycle)

1400 mg SC; days 1, 8, 15, 22, and 29

Cycles 2 to 3 (42-day cycles)

1400 mg SC every 2 weeks; days 1, 15, and 29

Stop for intensification treatment (high dose chemotherapy and ASCT) followed by SOC maintenance treatment

Each treatment cycle consists of a 42-day period.

Missed dose

The administration schedule must be carefully followed. If a planned dose of isatuximab is missed, administer the dose as soon as possible and adjust the treatment schedule accordingly, maintaining the treatment interval.

Dose adjustments

Dose reduction of isatuximab subcutaneous is not permitted. Dose delay or omission may be required. In case of Grade 3 or 4 neutropenia, or febrile neutropenia and/or neutropenic infection, see "Management of neutropenia" above. If patients experience systemic administration reactions or injection site reactions, see table 4 below for dose adjustment (see section 4.4).

Table 4: Isatuximab subcutaneous dose adjustments for SARs and ISRs

Adverse Reaction

Severity

Recommendations for isatuximab subcutaneous administration

Systemic administration reactions (SARs）

Grade 2 or Grade 3

- Stop current administration and do not complete it.

- Administer additional medication: diphenhydramine 25 mg IV (or equivalent) and/or methylprednisolone 100 mg IV (or equivalent) and/or other supportive care, as needed.

- In case of Grade 3: consider resuming treatment at the next planned administration.

3rd occurrence of Grade 3 or Grade 4

- Permanently discontinue isatuximab.

Injection site reactions（ISRs)

Grade 2

- During administration: Interrupt administration and resume it only after recovery to Grade ≤1 with pauses during the administration (if using CirCLIQ OBDS*) or a slower administration (if manual injection).

- Post- administration: Continue treatment after recovery to Grade ≤1.

Grade 3 or 4

- Permanently discontinue isatuximab.

NCI-CTCAE v5.0

* In case isatuximab subcutaneous administration using CirCLIQ OBDS needs to be paused, please refer to the OBDS instructions for use.

Special populations

Elderly

No dose adjustment is recommended in elderly patients (see sections 4.4, 4.8, and 5.2).

Patients with renal impairment

No dose adjustment of isatuximab is needed in patients with mild, moderate, severe, or end-stage renal impaired function (see section 5.2).

Patients with hepatic impairment

No dose adjustment is recommended in patients with mild hepatic impairment. Limited data are available in patients with moderate hepatic impairment and no data are available in patients with severe hepatic impairment, however, there is no evidence to suggest that dose adjustment is required in these patients (see section 5.2).

Paediatric population

The safety and effectiveness of isatuximab subcutaneous in children aged below 18 years of age have not been established. No data with isatuximab subcutaneous are available. Currently available data with intravenous formulation are described in sections 4.8, 5.1, and 5.2 but no recommendation on a posology for isatuximab can be made.

Method of administration

Sarclisa 1400 mg subcutaneous formulation is not intended for intravenous administration and should be given by subcutaneous injection only, using the doses specified. It is important to check the vial labels to ensure that the appropriate formulation (intravenous or subcutaneous formulation) and dose is being given to the patient as prescribed.

Sarclisa 1400 mg is for abdominal subcutaneous administration only, with CirCLIQ On-Body Delivery System (OBDS) or with a syringe and infusion set for manual administration. Refer to section 6.6 for isatuximab subcutaneous preparation and administration.

• Sarclisa 1400 mg is only for abdominal subcutaneous administration. Data are only available with an injection performed into the abdomen.

• Rotate the site of each subcutaneous administration.

• Do not inject other medications in the area where isatuximab subcutaneous is injected.

• Do not inject into areas where the skin is injured, tender, red, hot, has scars, or is excessively hairy.

Administration with CirCLIQ On-Body Delivery System

• Refer to the Instructions for Use for CirCLIQ OBDS provided with the device for full preparation and administration information.

Administration with syringe and infusion set for manual administration

Prepare injection site and insert needle

• Wipe injection site with an alcohol swab and allow it to dry.

• Avoid injecting within 5 cm around the belly button. Remove protective needle cover.

• Pinch skin at the injection site on the abdomen. It is important to pinch enough skin to inject under the skin and not into the muscle.

• Insert needle at a 45-degree angle with a quick, dart-like motion.

Note: Try to limit needle and syringe movement during the injection. If needed, secure the subcutaneous infusion set in place with a bandage.

Inject 10 mL of Sarclisa 1400 mg subcutaneously into the abdomen, over approximately 6 minutes.

Pause or slow down delivery rate if the patient experiences pain. In the event pain is not alleviated by pausing or slowing down delivery rate, a second injection site may be chosen on the opposite side of the abdomen to deliver the remainder of the dose.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Systemic administration reactions (SARs)In clinical trials with subcutaneous isatuximab (N = 522), SARs occurred in 16 patients (3.1%); 14 patients (2.7%) experienced only one episode. An SAR occurred at first administration in 10 patients (1.9%). They were mostly low grades (Grade 1 or 2) and resolved at the most within 3 days. The reported symptoms of SARs (all below 1%) were mainly pyrexia, dyspnoea, and sinus tachycardia. There was one Grade 3 episode of SAR in one patient that experienced hypertension and dyspnoea. In case of Grade ≥2 SARs, administration adjustments should be considered (see sections 4.2 and 4.8).

To decrease the risk and severity of SARs, patients should be pre-medicated prior to isatuximab subcutaneous administration with montelukast (at cycle 1 only), acetaminophen, diphenhydramine or equivalent; dexamethasone is to be used as both premedication and anti-myeloma treatment (see section 4.2).

Neutropenia

Neutropenia was reported in clinical trials with isatuximab subcutaneous or intravenous in combination therapies. With isatuximab subcutaneous combination therapies, a higher incidence of Grade 3 ‒ 4 neutropenia reported as laboratory abnormality was observed in patients with body weight ≤50 kg compared to patients with a higher body weight, with however similar incidences of neutropenic complications (see section 4.8).

Complete blood cell counts should be monitored periodically during treatment. Antibacterial and antiviral prophylaxis (such as herpes zoster prophylaxis) can be considered during treatment (see section 4.2). Patients with neutropenia should be monitored for signs of infection. No dose reductions of isatuximab subcutaneous are recommended. Isatuximab subcutaneous dose delays and the use of colony-stimulating factors (e.g. G-CSF) should be considered to mitigate the risk of neutropenia (see section 4.2).

Infections

Infections were reported in clinical trials with isatuximab subcutaneous or intravenous in combination therapies, with an incidence of 66.4% of patients, including Grade ≥3 infections reported in 29.9% of patients. Upper respiratory tract infection, pneumonia, and bronchitis were the most frequently reported infections (see section 4.8).

Patients receiving isatuximab subcutaneous should be closely monitored for signs of infection and appropriate standard therapy instituted. Antibacterial and antiviral prophylaxis (such as herpes zoster prophylaxis) should be considered during treatment (see section 4.2).

Second primary malignancies

Second primary malignancies (SPMs) were reported in clinical trials with isatuximab subcutaneous or intravenous in combination therapies (see section 4.8).

The overall incidence of SPMs in isatuximab-exposed patients (subcutaneous and intravenous formulations) is 5.4%. Monitor patients for the development of second primary malignancies and initiate treatment as indicated.

Tumour lysis syndrome

Cases of tumour lysis syndrome (TLS) have been reported in patients who received regimens containing isatuximab administered intravenously. Patients should be monitored closely and appropriate precautions taken.

Interference with serological testing (indirect antiglobulin test)

Isatuximab binds to CD38 on red blood cells (RBCs) and may result in a false positive indirect antiglobulin test (indirect Coombs test). This interference with the indirect Coombs test may persist for at least 6 months after the last administration of isatuximab. To avoid potential problems with RBC transfusion, patients being treated with isatuximab should have blood type and screen tests performed prior to the first administration. Phenotyping may be considered prior to starting isatuximab treatment as per local practice. If treatment with isatuximab has already started, the blood bank should be informed. Patients should be monitored for theoretical risk of haemolysis. If an emergency transfusion is required, non-cross-matched ABO/Rh-compatible RBCs can be given as per local blood bank practices (see section 4.5).

Interference with determination of complete response

Isatuximab is an IgG kappa monoclonal antibody that could be detected on both serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference may persist for at least 6 months after the last administration of isatuximab. In patients with persistent very good partial response, where interference is suspected, consider using a validated isatuximab-specific IFE assay (Sebia Hydrashift) to remove isatuximab interference and specifically visualize any remaining serum M protein, to facilitate determination of complete response (see section 4.5).

Educational materials

All prescribers who intend to prescribe isatuximab as well as healthcare professionals at blood banks/transfusion centres must ensure they have received and are familiar with the healthcare professional educational material prepared for the management of the risk of interference with serological testing. Prescribers must explain to the patients that isatuximab may affect the results of their serological testing for at least 6 months after their last dose of isatuximab. This is also explained in the patient card that prescribers must give to patients at time of the first dose of Sarclisa. The patients must be instructed to carry the card during treatment and for at least 6 months after the treatment has ended and to share it with their healthcare team.

Elderly

Data are limited in the population ≥85 years old (see section 4.8).

Body weight >120 kg

There is a potential for reduced efficacy with isatuximab subcutaneous in patients with a body weight >120 kg, due to the effect of body weight on exposure (see section 5.2).

4.5. Interaction with other medicinal products and other forms of interaction

The pharmacokinetics of subcutaneous isatuximab, and concomitant pomalidomide, carfilzomib, bortezomib, and lenalidomide are not expected to be influenced by their co-administration, as it was shown with intravenous isatuximab.

Interference with serological testing

Because CD38 protein is expressed on the surface of red blood cells, isatuximab, an anti-CD38 antibody, may interfere with blood bank serologic tests with potential false positive reactions in indirect antiglobulin tests (indirect Coombs tests), antibody detection (screening) tests, antibody identification panels, and antihuman globulin (AHG) crossmatches in patients treated with isatuximab (see section 4.4). This interference may persist for at least 6 months after the last administration of isatuximab. The interference mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt isatuximab binding or other locally validated methods. Since the Kell Blood group system is also sensitive to DTT treatment, Kell-negative units should be supplied after ruling out or identifying alloantibodies using DTT-treated RBCs.

Interference with serum protein electrophoresis and immunofixation tests

Isatuximab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M-protein) and may interfere with accurate response classification based on International Myeloma Working Group (IMWG) criteria (see section 4.4). This interference may persist for at least 6 months after the last administration of isatuximab. Because of this interference, Hydrashift assay was routinely used in IRAKLIA and IZALCO clinical studies for efficacy assessment to determine the complete response in patients with IgG kappa myeloma protein.

In patients with persistent very good partial response, where interference is suspected, consider using a validated isatuximab-specific IFE assay (Sebia Hydrashift) to remove isatuximab interference and specifically visualize any remaining serum M protein, to facilitate determination of complete response (see section 4.4).

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception

Women of childbearing potential treated with isatuximab should use effective contraception during treatment and for 7 months after cessation of treatment.

Pregnancy

There are no available data on isatuximab use in pregnant women. Animal reproduction toxicity studies have not been conducted with isatuximab. Immunoglobulin G1 monoclonal antibodies are known to cross the placenta after the first trimester of pregnancy. The use of isatuximab in pregnant women is not recommended.

Breast-feeding

It is unknown whether isatuximab is excreted in human milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which is decreasing to low concentrations soon afterwards; however, a risk to the breast-fed child cannot be excluded during this short period just after birth. For this specific period, a decision must be made whether to discontinue breast-feeding or to discontinue/abstain from isatuximab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Afterwards, isatuximab could be used during breast-feeding if clinically needed.

Fertility

No human and animal data are available to determine potential effects of isatuximab on fertility in males and females (see section 5.3).

4.7. Effects on ability to drive and use machines

Isatuximab has minor to moderate influence on the ability to drive and use machines. Fatigue and dizziness have been reported in patients taking isatuximab and this should be taken into account when driving or using machines.

4.8. Undesirable effects

Summary of the safety profile

The most frequent adverse reactions with isatuximab subcutaneous or intravenous in combination therapies (N = 2656) were infusion-related reactions (27.5%), diarrhoea (27.2%), neutropenia (25.1%), upper respiratory tract infection (23%), pneumonia (22%), and fatigue (20.7%). The most frequent serious adverse reaction was pneumonia (16.5%). Definitive study treatment discontinuation because of adverse reactions was reported in 10.2% of patients (due to pneumonia in 1.1% of patients). Adverse reactions with a fatal outcome during treatment were reported in 5.9% of patients (due to pneumonia in 1.9% of patients).

The safety profile of isatuximab 1400 mg subcutaneous (N = 522) in combination therapies was overall consistent with the known safety profile of isatuximab 10 mg/kg intravenous (N = 2134) in monotherapy or in combination therapies. Differences were observed in systemic administration reactions with a lower incidence reported with isatuximab subcutaneous (3.1%) versus isatuximab intravenous (33.5%). Injection site reactions associated with isatuximab subcutaneous administration were reported in 1.48% of injections (11.9% of patients), all Grade ≤2.

Tabulated list of adverse reactions

Adverse reactions are described by frequency category. Frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10 000 to <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

The adverse reactions were reported in clinical studies (see section 5.1) and post-market settings.

Isatuximab in combination with pomalidomide and dexamethasone (Isa-Pd)

The Table 5 reports the pooled safety data from 827 patients with relapsed and/or refractory multiple myeloma (RRMM) treated with isatuximab subcutaneous 1400 mg (307 patients) or with isatuximab intravenous 10 mg/kg (520 patients). Data include patients from IRAKLIA (EFC15951), TCD15484, ICARIA-MM (EFC14335) and TCD14079 studies.

Table 5: Adverse reactions reported in patients with multiple myeloma treated with isatuximab subcutaneous or intravenous formulation in combination with pomalidomide and dexamethasone

System organ class

Preferred term

Adverse reaction

Frequency

Incidence

(N = 827)

Any Grade

Grade ≥3

Infections and infestations

Pneumonia a

Very common

28.4%

22.0%

Upper respiratory tract infection

Very common

27.9%

2.1%

Neutropenic infection

Very common

16.9%

8.3%

Bronchitis

Very common

10.6%

1.6%

Covid-19

Very common

10.2%

1.8%

Herpes zoster

Common

1.2%

0.2%

Neoplasms benign, malignant and unspecified (incl cysts and polyps) b

Skin cancer

Common

4.2%

0.8%

Solid tumour (non-skin cancer)

Common

1.7%

1.0%

Haematology malignancy

Uncommon

0.5%

0.5%

Blood and lymphatic system disorders

Neutropenia c

Very common

51%

50.7%

Thrombocytopenia

Common

8.5%

7.9%

Anaemia

Common

6.9%

5.3%

Febrile neutropenia

Common

5.3%

5.3%

Lymphopenia

Not known

–

–

Immune system disorders

Anaphylactic reaction d

Uncommon

0.3%

0.3%

Metabolism and nutrition disorders

Decreased appetite

Common

5.3%

0.5%

Psychiatric disorders

Insomnia

Very common

16.7%

3.7%

Nervous system disorders

Peripheral sensory neuropathy

Very common

10.2%

0.5%

Dizziness

Common

8.9%

0.2%

Cardiac disorders

Atrial fibrillation

Common

4.0%

1.9%

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Very common

12.3%

2.3%

Cough

Very common

12.2%

0%

Gastrointestinal disorders

Diarrhoea

Very common

25.4%

1.5%

Constipation

Very common

18.4%

0.1%

Nausea

Very common

13.2%

0.5%

Vomiting

Common

8.1%

0.5%

Musculoskeletal and connective tissue disorders

Back pain

Very common

14.5%

1.6%

Arthralgia

Very common

10.8%

1.7%

Muscle spasms

Very common

10.6%

0.2%

General disorders and administration site conditions

Fatigue

Very common

24.2%

3.6%

Oedema peripheral

Very common

13.9%

0.7%

Pyrexia

Very common

10.2%

1.2%

Investigations

Weight decreased

Common

2.9%

0.1%

Injury, poisoning and procedural complications

Systemic administration reaction e With isatuximab intravenous f With isatuximab subcutaneous g

Injection site reactions e g

With isatuximab subcutaneous

Very common

Common

Common

31.5%

2.0%

9.8%

1.5%

0.3%

0%

a The term pneumonia is a grouping of terms.

b Based on second primary malignancies reported during study treatment period and during post-treatment period.

c Haematology laboratory values were recorded as TEAEs only if they led to treatment discontinuation and/or dose modification and/or fulfilled a serious criterion. The term neutropenia is a grouping of neutropenia and neutrophil count decrease.

d Based on post-marketing experience with intravenous isatuximab.

e See “Description of selected adverse reactions”.

f Based on isatuximab intravenous arms of isatuximab SC and IV clinical studies (N = 520).

g Based on isatuximab subcutaneous arms of isatuximab SC clinical studies (N = 307).

MedDRA 27.00

Isatuximab in combination with carfilzomib and dexamethasone (Isa-Kd)

The Table 6 reports the pooled safety data from 251 patients with RRMM treated with isatuximab subcutaneous 1400 mg or with isatuximab intravenous 10 mg/kg. Data include patients from IZALCO (ACT17453) and IKEMA (EFC15246) studies.

Table 6: Adverse reactions reported in patients with multiple myeloma treated with isatuximab subcutaneous or intravenous formulation in combination with carfilzomib and dexamethasone

System organ class

Preferred term

Adverse reaction

Frequency

Incidence

(N = 251)

Any Grade

Grade ≥3

Infections and infestations

Upper respiratory tract infection

Very common

39.4%

2.8%

Pneumonia a

Very common

30.3%

21.1%

Bronchitis

Very common

18.7%

1.6%

Nasopharyngitis

Very common

16.7%

0%

Covid-19

Very common

15.1%

2.4%

Respiratory tract infection

Very common

10.8%

1.2%

Influenza

Very common

10.0%

1.2%

Herpes zoster

Common

2.4%

0.4%

Neutropenic infection

Common

2.0%

0.4%

Neoplasms benign, malignant and unspecified (incl cysts and polyps) b

Skin cancer

Common

6.0%

1.6%

Solid tumour (non-skin cancer)

Common

2.8%

2.4%

Blood and lymphatic system disorders

Neutropenia c

Common

8.0%

7.2%

Anaemia

Common

6.0%

4.4%

Thrombocytopenia

Common

4.8%

3.6%

Febrile neutropenia

Common

1.2%

1.2%

Lymphopenia

Not known

–

–

Immune system disorders

Anaphylactic reaction d

Uncommon

0.3%

0.3%

Psychiatric disorders

Insomnia

Very common

21.5%

5.2%

Nervous system disorders

Peripheral sensory neuropathy

Very common

12.7%

0%

Dizziness

Common

4.4%

0%

Eye disorders

Cataract

Very common

13.1%

3.2%

Vascular disorders

Hypertension

Very common

31.5%

17.9%

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Very common

23.9%

4.4%

Cough

Very common

17.9%

0%

Gastrointestinal disorders

Diarrhoea

Very common

31.1%

2.0%

Nausea

Very common

16.7%

0%

Vomiting

Very common

13.9%

0.8%

Constipation

Very common

10.4%

0.4%

Musculoskeletal and connective tissue disorders

Back pain

Very common

19.9%

1.6%

Arthralgia

Very common

17.1%

1.6%

Muscle spasms

Very common

11.6%

0%

Pain in extremity

Very common

11.6%

0%

General disorders and administration site conditions

Fatigue

Very common

25.1%

4.4%

Asthenia

Very common

14.3%

1.6%

Oedema peripheral

Very common

13.5%

0.4%

Pyrexia

Very common

12.7%

1.6%

Injury, poisoning and procedural complications

Systemic administration reaction eWith isatuximab intravenous f With isatuximab subcutaneous g

Injection site reactions e g

With isatuximab subcutaneous

Very common

Common

Common

47.5%

2.7%

8.1%

0.6%

0%

0%

a The term pneumonia is a grouping of terms.

b Based on second primary malignancies reported during study treatment period and during post-treatment period.

c Haematology laboratory values were recorded as TEAEs only if they led to treatment discontinuation and/or dose modification and/or fulfilled a serious criterion. The term neutropenia is a grouping of neutropenia and neutrophil count decrease.

d Based on post-marketing experience with intravenous isatuximab.

e See “Description of selected adverse reactions”.

f Based on isatuximab intravenous clinical study (N = 177).

g Based on isatuximab subcutaneous clinical study (N = 74).

MedDRA 27.0

Isatuximab in combination with bortezomib, lenalidomide, and dexamethasone (Isa-VRd)

The Table 7 reports the pooled safety data from 904 patients with NDMM eligible or not for autologous stem cell transplantation, treated with isatuximab subcutaneous 1400 mg (141 patients) or with isatuximab intravenous 10 mg/kg (763 patients). Data include patients from IsaSoCut (IIT17756), GMMG-HD8 (IIT17041), IMROZ, TCD13983 and GMMG-HD7 (IIT15403) studies.

Table 7: Adverse reactions reported in patients with multiple myeloma treated with isatuximab subcutaneous or intravenous formulation in combination with bortezomib, lenalidomide, and dexamethasone

System organ class

Preferred term

Adverse reaction

Frequency

Incidence

(N = 904)

Any Grade

Grade ≥3

Infections and infestations

Pneumonia a

Very common

19.9%

14.7%

Upper respiratory tract infection

Very common

15.2%

0.7%

Bronchitis

Very common

11.8%

1.7%

Covid-19

Very common

11.3%

1.5%

Neutropenic infection

Common

4.8%

1.8%

Neoplasms benign, malignant and unspecified (incl cysts and polyps) b

Skin cancer

Common

3.3%

1.0%

Solid tumour (non-skin cancer)

Common

2.3%

1.5%

Haematology malignancy

Uncommon

0.3%

0.1%

Blood and lymphatic system disorders

Neutropenia c

Very common

33.7%

28.8%

Thrombocytopenia

Very common

13.2%

10.7%

Lymphopenia

Very common

12.8%

11.2%

Anaemia

Common

8.2%

4.3%

Febrile neutropenia

Common

1.5%

1.4%

Immune system disorders

Anaphylactic reaction d

Uncommon

0.2%

0.2%

Psychiatric disorders

Insomnia

Very common

12.3%

1.9%

Nervous system disorders

Peripheral sensory neuropathy

Very common

29.2%

3.3%

Polyneuropathy

Very common

10.0%

2.1%

Dizziness

Common

7.0%

0.2%

Eye disorders

Cataract

Very common

15.8%

6.1%

Gastrointestinal disorders

Diarrhoea

Very common

29.9%

5.0%

Constipation

Very common

22.9%

1.7%

Vomiting

Common

5.4%

0.3%

Skin and subcutaneous tissue disorders

Rash

Very common

10.6%

2.0%

Musculoskeletal and connective tissue disorders

Back pain

Very common

11.9%

1.5%

General disorders and administration site conditions

Oedema peripheral

Very common

17.1%

0.3%

Asthenia

Very common

14.8%

2.0%

Fatigue

Very common

14.3%

3.0%

Pyrexia

Very common

10.4%

1.0%

Investigations

Weight decreased

Common

6.1%

0.4%

Injury, poisoning and procedural complications

Systemic administration reaction e

With isatuximab intravenous fWith isatuximab subcutaneous g

Injection site reactions e g

With isatuximab subcutaneous

Very common

Common

Very common

19.9%

5.7%

18.4%

1.2%

0%

0%

a The term pneumonia is a grouping of terms.

b Based on second primary malignancies reported during study treatment period and during post-treatment period.

c The term neutropenia is a grouping of neutropenia and neutrophil count decrease.

d Based on post-marketing adverse reactions experience with intravenous isatuximab

e See “Description of selected adverse reactions”.

f Based on isatuximab intravenous arms of isatuximab SC and IV clinical studies (N = 763).

g Based on isatuximab subcutaneous arms of isatuximab SC clinical studies (N = 141).

MedDRA 27.0

Description of selected adverse reactions

Systemic administration reactions (SARs)

In clinical trials (IRAKLIA, IZALCO, IsaSoCut, GMMG-HD8, and TCD15484, N = 522), SARs related to isatuximab subcutaneous were reported in 3.1% of patients. SARs occurred at the first administration in 1.9% of patients and at subsequent administrations in 1.3% of patients. For patients who experienced SARs, SARs occurred from the day of the administration (42.1% of patients) to 3 days after the administration (15.8% of patients). Grade 1 SARs were reported in 1.9% of patients, Grade 2 in 1.0%, and Grade 3 in 0.2%. No Grade 4 or 5 SARs were reported. All SARs resolved, within 1 day in 42.1% of patients, within 2 days in 15.8% of patients, and within at least 3 days in 42.1% of patients. No isatuximab SC administrations were interrupted or permanently discontinued due to SARs (see section 4.4).

In multiple myeloma clinical trials with intravenous isatuximab, anaphylactic reactions have been reported in association with infusion reactions in 0.3% of patients. In the postmarketing setting, fatal cases of anaphylactic reactions have been reported with intravenous isatuximab.

Injection site reactions (ISRs)

In clinical trials (IRAKLIA, IZALCO, IsaSoCut, GMMG-HD8 and TCD15484, N = 522), injection site reactions (ISRs) with isatuximab subcutaneous administration were reported in 11.9% (10% Grade 1 and 1.9% Grade 2) of patients and in 1.48% of injections (154 episodes out of 10 422 injections). No grade 3, 4, or 5 ISRs were reported. The ISRs occurred the day of the administration in 85.9% of patients. All ISRs resolved, 74.3% of them resolved on the same day. With Isa-SC + Pd and Isa-SC + Kd, 5% of patients experienced symptoms of ISR (not collected in Isa-VRd studies). The most frequent (>1%) symptoms of ISR were injection site erythema (3.4%), injection site swelling (1.8%), and injection site pain (1.6%).

In IZALCO, the incidence of ISR (8.1% of patients) was similar with CirCLIQ OBDS administration (0.86% of CirCLIQ OBDS injections) and manual administration (1.34% of manual injections).

In IRAKLIA, of the 12 patients (4.6% of patients, 55 administrations) with at least one Sarclisa subcutaneous administration performed at home, 1 ISR was reported. The ISR was a single grade 1 episode that resolved within the same day.

Infections

In clinical studies of isatuximab intravenous and subcutaneous formulations (N = 2656), the most commonly reported infections were upper respiratory tract infection (23.0%), pneumonia (22.0%), and bronchitis (11.0%). Grade ≥3 infections were reported in 29.9% of patients including 16.6% Grade ≥3 pneumonia). Serious infections were reported in 29.0% of patients. The most frequent serious infection was pneumonia (16.5%). Discontinuations from treatment due to infection were reported in 4.0% of patients. Fatal infections were reported in 3.4% of patients. Neutropenic complications have been observed in 9.0% of patients, including 2.5% of febrile neutropenia and 7.2% of neutropenic infections.

Second primary malignancies

In clinical trials of isatuximab intravenous and subcutaneous formulations (N = 2656), second primary malignancies (SPMs) were reported in 144 patients (5.4%), with a rate of 3.0 per 100 person-years. SPM were skin cancer in 89 patients (3.4%), solid tumours other than skin cancer in 52 patients (2.0%), and haematological malignancy in 8 patients (0.3%). The most frequently reported SPMs were basal cell carcinoma and squamous cell carcinoma of skin (1.5% and 1.6% of patients, respectively). In studies that collected this information (N = 2518), permanent full treatment discontinuation due to SPM occurred in 26 patients (1.0%).

Cardiac failure

In clinical trials of isatuximab intravenous and subcutaneous formulations (N = 2656), cardiac failure was reported in 38 patients (1.4%). In patients receiving intravenous or subcutaneous isatuximab in combination with carfilzomib and dexamethasone (IZALCO and IKEMA), 10 cases (4.0%) of cardiac failure with 5 serious cases (2.0%) were reported. In patients receiving intravenous isatuximab in IKEMA (Isa-IV +Kd vs Kd), cardiac failure was reported in 7.3% of patients with the Isa-IV + Kd arm and in 6.6% of patients with the Kd arm. Serious cardiac failure was observed in 4.0% of patients in the Isa-IV + Kd arm and in 3.3% of patients in the Kd arm (see the Summary of Product Characteristics of carfilzomib).

Haematology laboratory values

Table 8: Haematology laboratory abnormalities during the on-treatment period in patients receiving Isa-SC + Pd or Isa-IV + Pd

Laboratory parameter

Subcutaneous or intravenous Isatuximab + Pomalidomide + Dexamethasone

(N = 827)

All grades

Grade 3

Grade 4

Neutropenia

96.1%

30.1%

50.9%

Anaemia

96.8%

21.6%

0%

Lymphopenia

92.8%

41.5%

9.8%

Thrombocytopenia

85.0%

13.8%

13.8%

The denominator used for the percentage calculation is the number of patients with at least 1 evaluation of the laboratory test during the considered observation period.

CTCAE version: 5

Table 9: Haematology laboratory abnormalities during the on-treatment period in patients receiving Isa-SC + Kd or Isa-IV+ Kd

Laboratory parameter

Subcutaneous or intravenous Isatuximab + Carfilzomib + Dexamethasone

(N = 251)

All grades

Grade 3

Grade 4

Anaemia

100%

23.2%

0%

Lymphopenia

93.6%

52.8%

15.2%

Thrombocytopenia

93.2%

16.4%

11.2%

Neutropenia

56.4%

17.2%

2.4%

The denominator used for the percentage calculation is the number of patients with at least 1 evaluation of the laboratory test during the considered observation period.

CTCAE version: 5

Table 10: Haematology laboratory abnormalities during the on-treatment period in patients receiving Isa-SC + VRd or Isa-IV + VRd

Laboratory parameter

Subcutaneous or intravenous Isatuximab + Bortezomib + Lenalidomide + Dexamethasone

(N = 904)

All Grades

Grade 3

Grade 4

Anaemia

90.5%

8.6%

0%

Lymphopenia

77.9%

30.7%

11.3%

Thrombocytopenia

58.3%

9.0%

7.8%

Neutropenia

59.2%

19.7%

9.5%

The denominator used for the percentage calculation is the number of patients with at least 1 evaluation of the laboratory test during the considered observation period.

CTCAE version: 5

Elderly patients

Of the total number of patients in clinical studies of isatuximab subcutaneous and intravenous (N = 2656), 43.8% (1165 patients) were less than 65, 41.4% (1099 patients) were 65 ‒ 74, and 14.8% (392 patients) were 75 or older. Differences in safety were observed between older versus younger age groups. Grade ≥3 TEAEs were reported in 69.0% of patients less than 65, 80.2% of patients 65 ‒ 74 and 78.8% of patients 75 or older. Grade ≥3 neutropenia occurred at a higher frequency in older patients with incidences of 19.4% in patients less than 65, 24.8% in patients 65 – 74, and 28.6% in patients 75 or older. Grade ≥3 infection occurred at a higher frequency in older patients with incidences of 24.2% in patients less than 65, 34.2% in patients 65 – 74, and 34.7% in patients 75 or older. Grade 5 TEAEs were reported in 5.2% of patients less than 65, 7.1% of patients 65 ‒ 74, and 10.5% of patients 75 or older. Serious TEAEs were reported in 45.5% of patients less than 65, 56.6% of patients 65 ‒ 74, and 59.9% of patients 75 or older. TEAEs leading to definitive treatment discontinuation were reported in 6.0% of patients less than 65, 12.3% of patients 65 ‒ 74, and 13.0% of patients 75 or older.

In Newly Diagnosed Multiple Myeloma studies (N = 904), Grade 5 TEAEs were reported in 1.8% of patients less than 65, in 6.4% of patients 65 ‒ 74, and in 11.8% of patients 75 or older.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity to isatuximab.

Anti-drug antibodies (ADA) were uncommonly reported after subcutaneous isatuximab administrations (4.9% in studies in RRMM and 15.9% in studies in NDMM). In the small subgroup of ADA positive patients, there was no evident effect of ADA on isatuximab pharmacokinetics, safety, or efficacy.

Paediatric population

The safety of isatuximab in children has not been established. No data are available with subcutaneous isatuximab.

In a phase 2 single-arm study conducted with intravenous isatuximab in 67 paediatric patients with relapsed or refractory acute lymphoblastic leukaemia or acute myeloid leukaemia, all evaluable for safety, Grade ≥3 TEAEs was reported in 79.1% of patients. The most common Grade ≥3 TEAEs occurring in >10% of patients included febrile neutropenia (41.8%), septic shock (11.9%), and stomatitis (10.4%). The addition of intravenous isatuximab to standard chemotherapies did not modify the expected safety profile observed with standard chemotherapies in this paediatric population and was consistent with isatuximab safety profile for adults with multiple myeloma in ICARIA-MM and IKEMA studies (see section 4.2).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Signs and symptoms

There has been no experience of overdose of isatuximab in clinical studies. Doses of subcutaneous isatuximab up to 1400 mg have been administered in clinical studies.

Management

There is no known specific antidote for isatuximab overdose. In the event of overdose, monitor the patients for signs or symptoms of adverse reactions and take all appropriate measures immediately.